2. Definition
Standard structure for representing the planned
sequence of events and the treatment plan of a trail.
Plan for a precise procedure to be followed in a
clinical trail, including timing of events, choice of
control group, method of allocating treatments,
blinding methods.
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3. Study Design
The choice of design depends on the goal of the trial
Choice also depends on the population, knowledge of the
intervention
Choose mentor wisely
Get an epidemiologist/ statistician on board at start
Should be Flexible, appropriate, efficient, economical
Should give smallest experimental error & high reliability &
validity
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4. Phase I Design
Typical/Standard Design
Based on tradition, not so much on
statistical theory
Dose escalation to reach maximum tolerated
dose (MTD)
Dose escalation often based on Fibonacci Series
1 2 3 5 8 13 . . . .
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5. Typical Scheme
1. Enter 3(5) patients at a given dose
2. If no toxicity, go to next dosage and repeat step 1
3. a. If 1 patient has serious toxicity, add 3 more
patients at that dose (go to 4)
b. If 2/3 have serious toxicity, consider MTD
4. a. If 2 or more of 6 patient show toxicity, MTD
reached (perhaps)
b. If 1 of 6 has toxicity, increase dose and go back
to
step 1
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6. Standard Phase I Design
Designed to find dose where 1/3 of patients
experience dose limiting toxicity (DLT)
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7. Therapeutic Index for a new
drug
Therapeutic Index
Toxic Dose
Minimally Effective Dose
Dose
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8. Phase II Design
Goal
Screen for therapeutic activity
Further evaluate toxicity
Test using MTD from Phase I
If drug passes screen, test further
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9. Phase II Design
No control
Goal is to reject ineffective drugs ASAP
Decision I: Drug is unlikely to be effective in x% of
patients
Decision II: Drug could be effective
in x% of patients
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10. Phase III Introduction
Use of proper control group necessary due to:
Natural history of most diseases
Variability of a patient's response to intervention
No comparison groups needed when results dramatic:
Penicillin for pneumococcal pneumonia
Rabies vaccine
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11. Phase III Design
Comparative Studies
Experimental Group vs. Control Group (Placebo
/ Comparator)
Placebo made to look like a study drug
Randomized Control Trial (RCT) is the gold
standard
Eliminates several sources of bias
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12. Purpose of Control Group
To allow discrimination of patient outcomes caused by
experimental intervention from those caused by other factors
Natural progression of disease
Observer/patient expectations
Other treatment
Fair comparisons
Necessary to be informative
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13. Choice of Control Group
Goals of Controlled Clinical Trials
Types of Control Groups
Significance of Control Group
Assay Sensitivity
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14. Considerations in Choice of
Control Group
Available standard therapies
Adequacy of the control evidence for the chosen design
Ethical considerations
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15. Significance of Control
Group
Inference drawn from the trial
Ethical acceptability of the trial
Degree to which bias is minimized
Type of subjects
Kind of endpoints that can be studied
Credibility of the results
Acceptability of the results by regulatory
authorities
Other features of the trial, its conduct, and
interpretation
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16. Randomized Control Clinical Trial
Patients assigned at random to either treatment(s) or control
Each patient has the same chance of receiving any of the treatments
under study
Allocation of treatments to participants is carried out using a chance
mechanism so that neither the patient nor the physician know in
advance which therapy will be assigned
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18. Advantages of RCT
Considered to be “Gold
Standard”
Randomization "tends" to
produce comparable groups
Randomization produces valid
statistical test
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19. Disadvantages RCT
1. Recruitment
Twice as many new patients
2. Acceptability of Randomization Process
Some physicians will refuse
Some patients will refuse
3. Administrative Complexity
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20. Treatment Studies
Randomized controlled trial
Non-blind trial
Single-blind randomized trial
Double-blind randomized trial
Triple-blind randomized trial
Nonrandomized trial (quasi-experiment)
Interrupted time series design (measures on a sample
or a series of samples from the same population are
obtained several times before and after a manipulated
event or a naturally occurring event) - considered a
type of quasi-experiment
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21. Non-Blind Trial / Open Trial
Researchers as well as patients know full details
of the treatment
Usually this kind of study design is used in
bioequivalence studies
Single-Blind Trial
Researchers know the detail of treatment but
patient does not
Since the researcher knows, it is possible for the
researcher to treat the patient differently or to
subconsciously hint to the patient important
treatment-related details, thus influencing the
outcome of the study
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22. Double-Blind Trial
Neither research staff nor study subjects know
the detail of treatment
Double-blind trials are preferred, as they tend
give the most accurate results
Triple-Blind Trial
Subject, researcher and person administering
treatment (often a pharmacist/ statistician) are
blinded
it connotes an additional layer of security to
prevent undue influence of study results by
anyone directly involved with the study
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23. Cluster Randomization Designs
• Groups (clinics, communities) are randomized to treatment
or control
• Examples:
• Community trials on fluoridization of water
• Breast self examination programs in different clinic setting
• Advantages
• Sometimes logistically more feasible
• Avoid contamination
• Allow mass intervention, thus “public health trial”
• Disadvantages
• Effective sample size less than number of subjects
• Many units must participate to overcome unit-to-unit variation,
thus requires larger sample size
• Need cluster sampling methods
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24. Commonly used Phase III
Design
Open label trial
Parallel trial
Cross over trial
Randomized control trial
Cohort study
Prospective study
Retrospective study
Replicate design
Factorial design
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26. Open label trial
The situation when both the researcher and the
participant in a research study know the treatment the
participant is receiving.
Open-label trials may be appropriate for comparing
two very similar treatments to determine which is most
effective.
An open-label trial may be unavoidable under some
circumstances, such as comparing the effectiveness of a
medication.
Open-label trials may also be uncontrolled, with all
participants receiving the same treatment.
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27. Parallel Study
A parallel designed clinical trial compares the results of a
treatment on two separate groups of patients
Measures the standard deviation of repeated
observations in the same individual
Advantage
Simple, General Use
Valid Comparison
Disadvantage
Require greater sample size
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28. Parallel Design
Screen
Randomize
Study Treatment A vs. Treatment B in different groups
E.g. CAST (Cardiac Arrhythmia Suppression Trial ) DCCT
(Diabetes Control and Complications Trial )
Treatment A
Treatment B
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29. Crossover Study
A crossover study compares the results of a two
treatment on the same group of patients
Crossover designs are generally not used in
vaccine trials because the immune system is
permanently affected (or at least affected for a
long time). Thus, carry over effects are always
present
Measures the standard deviation of the
difference between two measurements in the
same individual
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30. Cross Over Design
Scheme
Period
Group I II
AB 1 TRT A TRT B
BA 2 TRT B TRT A
Advantage
Each patient their own control
Smaller sample size
Disadvantage
Not useful for acute disease
Disease must be stable
Assumes no period carry over
If carryover, have a study half sized
(Period I A vs. Period I B)
Washout
Period
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32. Run-In Design
Problem:
Non-compliance by patient may seriously impair
efficiency and possibly distort conclusions
Possible Solution: Drug Trials
Assign all eligible patients a placebo to be taken for a
“brief” period of time. Patients who are “judged”
compliant are enrolled into the study. This is often
referred to as the “Placebo Run-In” period.
Can also use active drug to test for compliance
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34. Examples of Run-In Trials
Cardiac Arrhythmia Suppression Trial (CAST)
Diabetes Control and Complications Trial (DCCT)
Physicians Health Study (PHS)
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35. Cohort Study
A cohort is a group of people who share a common
characteristic or experience within a defined period e.g are
exposed to a drug or a vaccine together
The comparison group may be the general population from
which the cohort is drawn, or it may be another cohort of
persons thought to have had little or no exposure to the
substance under investigation, but otherwise similar.
Alternatively, subgroups within the cohort may be compared
with each other.
Cohort studies are expensive to conduct & take a long
follow-up time to generate useful data. Some cohort studies
track groups of children from their birth, and record a wide
range of information (exposures) about them.
The value of a cohort study depends on the researchers'
capacity to stay in touch with all members of the cohort.
Some of these studies have continued for decades.
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37. Advantages of cohort study
Study design does not require strict random assignment
of subjects.
As in the case of smoking vs. non-smoking cohort study,
random assignment is not a feasible or ethical
alternative. (Who wants to be assigned to a smoking
group if he/she is non-smoker?).
Appealing and useful technique because it is highly
flexible.
In some instances, a cohort analysis can be less
expensive than experiments or surveys.
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38. Disadvantages of cohort study
To assess whether associations between cohort and dependent
variables derived from the studies are of a causal nature or not.
Threats to validity: influence of factors over which the investigators
most often do not have full control.
Because of the lack of randomization in the cohort design, the two
groups may differ in ways other than in the variable under study.
For e.g., if the subjects who smoke tend to have less money than
the non-smokers, and thus have less access to health care, that
would exaggerate the difference between the two groups.
Time consuming so tend to change over the course of the study
(People die, move away, or develop other conditions, new and
promising treatments arise, and so on.)
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39. Prospective study
A prospective study is a cohort study that follows over
time a group of similar individuals who differ with
respect to certain factors under study, in order to
determine how these factors affect rates of a certain
outcome.
For eg, middle-aged truck drivers who vary in terms of
smoking habits, in order to test that after 20-year
incidence rate of lung cancer will be highest among
heavy smokers, followed by moderate smokers, and
then nonsmokers.
The prospective study is important for research on the
etiology of diseases and disorders in humans.
It can be more expensive.
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40. Prospective Cohort Study Design
The Present The Future
Population
Sample
Risk Factor
No Risk Factor
Disease No Disease
Disease No Disease
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41. Advantages
Prospective cohort study data is the longitudinal
observation of the individual through time, and the
collection of data at regular intervals, so recall error is
reduced.
Temporal relationship established
Multiple outcomes can be studied
Good choice for rare exposure situation
Investigator defines and applies outcome criteria
Disadvantages
Hard to select and maintain a “non-exposed” group
Loss to follow-up problem for long induction times
Expensive
Changes can take place over time in both exposure and
outcome assessment
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42. Retrospective trial
Retrospective means to take a look back at
events that aleready have taken place (like pt’s
medical history)
Also called a historic cohort study, is a medical
research study in which the medical records of
groups of individuals who are alike in many
ways but differ by a certain characteristic.
For example, Long-Term Mortality after Gastric
Bypass Surgery
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44. Advantages of Retrospective Study
Inexpensive
Uses existing records
Allows study of rare occurrences
Easier to assess conditions where there is a
long latency between exposure and disease
Can generate hypothesis that is then tested
prospectively (quality improvement initiatives)
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45. Disadvantages of Retrospective Study
Relies on accuracy of written record or recall of
individuals
Important data may not be available
Difficult to control bias and confounders: no
randomization, no blinding
May be impossible to access important
information (restricted by statute or institutional
regulations)
Difficult to establish cause and effect
Results are, at best, hypothesis-generating
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46. Replicate design
The experiment should be repeated more than once,
thus each T/t is many experimental units instead of
one.
Typically four-period design
Each product administered twice
Intra-subject variability
Different approaches possible
Average bioequivalence
Individual bioequivalence
Period
1
Period
2
Period
3
Period
4
Sequence
1
T R R T
Sequence
2
R T T R
Sequence
3
T T R R
Sequence
4
R R T T
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47. Advantages
More information available
Different approaches to assessment possible
Disadvantages
Bigger commitment for volunteers
More administrations to healthy volunteers
More expensive to conduct
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48. Factorial design
Designs which include multiple independent variables are
known as factorial designs.
If we were looking at GENDER and ,TIME OF EXAM, these
would be two independent factors
GENDER would only have two levels: male or female
TIME OF EXAM might have multiple levels, e.g. morning,
noon or night
Depends on three pieces of information:
The number of independent variables
The number of levels of each independent variable
The kind of independent variable
Between Groups
Within Subjects (or Repeated Measures)
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49. If there is only one independent variable then
The design is a one-way design (e.g. does coffee drinking influence
exam scores)
If there are two independent variables
The design is a two-way design (e.g. does time of day or coffee
drinking influence exam scores).
If there are three independent variables
The design is a three-way design (e.g. does time of day, coffee drinking
or age influence exam scores).
E.g.: When patients are being treated with a combination of drugs, as is
current practice for HIV infection, a new drug may be evaluated by
testing it in combination with other drugs rather than by itself. A
factorial design trial may be used for this purpose. A simple factorial
design would have one group testing therapy A, another testing
therapy B, a third group testing A and B combined, and a control
group testing neither A nor B.
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51. Advantages
A greater precision can be obtained in estimating the
overall main factor effects.
Interaction between different factors can be explored.
Additional factors can help to extend validity of
conclusions derived.
Factorial designs are considered an efficient way to test
medicines in combination, but their results are not
always easy to interpret.
Disadvantages
Experimental error like replicated
Lesser attractive
More subjects
More expensive
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52. Other Types of trial
Superiority trials are designed to demonstrate that one treatment is
more effective than another.
Non-inferiority trials are designed to demonstrate that a treatment
is at least not appreciably worse than another.
Would have beaten placebo if a placebo arm had been included
(regulatory)
The question is whether new (easier or cheaper) treatment is as
good as the current treatment
Equivalence trials are designed to demonstrate that one treatment is
as effective as another by more than some margin
A longitudinal study research subjects over two or more points in
time; by contrast, while a cross-sectional study assesses research
subjects at one point in time.
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